1. Field of the Invention
The present invention relates to a process for the preparation of a cyclopropylacetylene derivative, an intermediate for the synthesis of the cyclopropylacetylene derivative and a process for the preparation of the same. The cyclopropylacetylene derivative produced by the process of the present invention is useful as an intermediate in synthesis of a compound having a cyclopropane skeleton, for example, a benzoxazinone derivative (L-743726), which has anti-HIV activity (Tetrahedron Letters, Vol. 36, page 8937 (1995)).
2. Description of the Background
Recently, a large number of physiologically active substances having a cyclopropane skeleton have been discovered. Examples of known methods of producing cyclopropylacetylene, which is useful as an intermediate for the synthesis of these compounds, include: (I) a method in which 5-chloropentyne is reacted with n-butyllithium (Tetrahedron Letters, Vol. 36, page 8937 (1995)); and (2) a method in which cyclopropyl methyl ketone is reacted with phosphorus pentachloride in carbon tetrachloride to produce 1,1-dichloro-1-cyclopropylethane, which is subsequently dehydrochlorinated by potassium tert-butoxide (Synthesis page 703 (1972)).
However, in method (1), the yield of the raw starting material 5-chloropentyne in the reaction by which it is produced is as low as 57% (Journal of American Chemical Society, Vol. 67, page 484 (1945)), and method (2) gives many byproducts and, therefore, produces relatively low yields of the target product. Therefore, these methods are of limited industrial utility for the production of cyclopropylacetylene.
Another method by which cyclopropylacetylene is prepared requires the reaction of a propynol derivative with an alkyl (di)halide in liquid ammonia in the presence of lithium amide to give an acetylene derivative (Bulletin de la Societe Chimique de France, pages 201-204 (1968)). However, no method of transforming the obtained acetylene derivative to a compound having a cyclopropane skeleton is disclosed or suggested therein.
Another reaction which is known is the ethynylation of cyclopropylacetylene with acetone or cyclopropyl methyl ketone to give 2-methyl-4-cyclopropyl-3-butyn-2-ol or 2,4-dicyclopropyl-3-butyn-2-ol (Izvetiya Akademii Nark SSSR, Seriya Khimicheskaya, pages 1339-1344 (1978)), but no description for the reverse reaction is provided.